Fluorocarbon compounds and their formulations have numerous applications in human and veterinary medicine as therapeutic and diagnostic agents. Fluorocarbons have many potential applications in the biomedical field, as blood substitutes, or more generally, as carriers in applications wherein oxygen must be supplied to organs and tissues, for example, in the treatment of cardio- and cerebrovascular disease, angioplasty, in organ preservation and in cancer therapy. Fluorocarbon formulations are also useful in diagnostic procedures, for example as contrast agents, and in the field or veterinary therapy (Riess, J. G., Hemocompatible Materials and Devices: Prospectives Towards the 21st Century, Technomics Publ. Co, Lancaster, Pa. USA, Chap 14 (1991); Vox Sanguinis., Vol. 61:225-239 (1991). One commercial biomedical fluorocarbon emulsion, Flusol.RTM., (Green Cross Corp., Osaka, Japan), is presently used, for example, as an oxygen carrier to oxygenate the myocardium during percutaneous transluminal coronary angioplasty (R. Naito, K. Yokoyama, Technical Information, Series n.degree. 5 and 7, 1981).
The dispersed phase of fluorocarbon emulsions must have a stable particle size to be suitable for biomedical use. One of the drawbacks of the Fluosol emulsion is its low stability; the particle size of fluorocarbon emulsions such as Fluosol.RTM. can be maintained only if they are transported and stored in the frozen state. The frozen emulsions are then defrosted and mixed with two annex solutions before use. These storage requirements seriously limit the field of application of Fluosol. Although more stable fluorocarbon emulsions are being developed (Oxygent.RTM. and Imagent.RTM., Alliance Pharmaceutical Corp., San Diego, Calif.), it is desirable to have fluorocarbon emulsions that are stable enough to store for long periods without refrigeration. Such storage stability would extend the use of fluorocarbons beyond medical facilities in order to meet, for example, the requirements of the army and civil defense. It is also desirable to control particle sizes to adapt the emulsion characteristics to specific applications.
Fluorocarbons are oily substances that are immiscible with water, and therefore fluorocarbon-in-water emulsions, such as Fluosol.RTM. and Oxygent.RTM., are presently prepared using lecithins and/or poloxamers of the Pluronic F-68.RTM. type as surfactants to disperse the fluorocarbon and stabilize the emulsion. Surfactants are commonly amphiphilic compounds having a hydrophobic end region and a hydrophilic end region. Lecithins have a hydrophobic end region comprising a hydrocarbon groups which have a low affinity for fluorocarbons. It is desirable to improve the affinity of the surfactant film for the fluorocarbon phase and to reduce the interfacial tension between the fluorocarbon and aqueous phases. (Riess, J. G., Competes Rendus du 2.sup.eme Congres Mondial des Agents de Surface (Paris, May 1988), ASPA 4:256-263 (1988)).
Several strategies can be employed to overcome this disadvantage of the emulsifying surfactants described. One approach is to develop more effective surfactants, for example, those having a hydrophobic end which is fluorophilic, for use in the preparation of classic emulsions. Efforts in this direction have led to new fluorinated surfactants such as those described in the documents EP-A- 0 255 443, EA-A-A 0 311 473 and WO 90/15807.
Another strategy is to prepare microemulsions, i.e., preparations of compounds which organize themselves spontaneously into dispersed systems (H. L. Rosano and W. E. Gerbacia, U.S. Pat. No. 3,778,381, Dec. 11, 1973; and G. Mathis, J. J. Delpuech, FR-A-2 515 198, 3.29.1983). In an example of a microemulsion described by Cecutti et al. Eur. J. Med. Chem., 24, 485-492 (1989), the dispersed phase is itself totally constituted of mixed hydrocarbon/fluorocarbon molecules. However, this strategy is not generally applicable to fluorocarbons, particularly those of the examples described in the present invention. Moreover, it is still totally uncertain whether the intravenous administration of microemulsions is safe. To our knowledge, no example of such administration exists in human medicine, whereas the classical emulsions, such as the lipidic emulsions for parenteral nutrition are abundantly used.
It would be advantageous to be able to emulsify any fluorocarbon chosen solely on the basis of its own advantageous properties and its efficacy, without regard to the problem of emulsification. For example, it would be advantageous to be able to prepare stable emulsions of perfluorooctyl bromide (PFOB, perflubron.RTM., Alliance Pharmaceutical Corp., La Jolla, Calif.) on account of its radiopacity, and of its potential as a contrast agent in diagnostics. It would also be advantageous to set the particle size in the emulsion at a value chosen a priori.